Adverse challenges in the perinatal period may alter nociceptive sensitivity in later life

Abstract

Chronic inflammatory and neuropathic pain states are poorly understood, and currently inadequately treated. Clinically, the symptoms of such pain states include allodynia (interpretation of innocuous stimuli as noxious), hyperalgesia (increased sensitivity to noxious stimuli) and spontaneous (non-evoked) pain. Additionally, chronic pain states are often associated with affective disorders such as anxiety and depression which can further reduce the individual’s quality of life. It is highly likely that neuropathic pain could occur in combination with chronic inflammation, for example as a result of post-surgical infection. When such injuries occur in early life, during the continuing development of the nervous system, it is possible that longterm adverse changes in sensory processing may occur. To investigate this, we have developed a rodent model of chronic pain with both a neuropathic and inflammatory component, designed to investigate the consequence of these to injuries coinciding. Furthermore, we are also investigating the effect of gestational stress, which has been shown to alter the stress responsiveness of the offspring and may also affect pain processing. To study the effect that prenatal stress may have on pain processing, we have utilised the rodent resident/intruder paradigm as a model of social stress to determine the outcomes of the combination of these adverse perinatal events. We find that a combined inflammatory and neuropathic injury in the adult rat increases sensitivity to both mechanical and thermal stimuli and also increases spontaneous pain, when compared to inflammation or nerve injury alone. We show that neuropathic pain can be induced in neonatal (P8) rats; however there is little response to inflammation at P8 and a combination of these two injuries does not have the additive effect on sensitivity that occurs in the adult. Upon recovery from neonatal nerve injury, we find that a subsequent noxious challenge (formalin) alters nocifensive behaviour, when compared to the formalin response of naïve (no prior injury) animals, indicating long-lasting changes to nociceptive processing. Interestingly, when nerve injury is carried out in adult animals, nocifensive behaviour in response to formalin is not altered compared to naïve controls. Calcium entry through the NMDA receptor and subsequent CaM Kinase IIα activation has been implicated as a crucial factor in long term potentiation (LTP) and the maintenance of sensitised states. In adult models of chronic pain, which may involve LTP mechanisms, we have shown an increased association of CaM Kinase IIα with NR2A/B spinal immunoprecipitates ipsilateral to injury. Furthermore, a different mechanism may be involved in neonatal pain states, as we have shown that spinal CaM Kinase IIα expression increases with development and is present at very low levels at the time of surgery in our pain models. Additionally, a number of other proteins associated with the NMDA receptor complex are developmentally regulated, and their involvement in the initiation and maintenance of chronic pain is likely to differ between the adult and the neonate. We further show that exposure to prenatal stress does not alter the thresholds to mechanical stimuli in adult or early life pain models, however the combination of prenatal stress and postnatal injury results in an enhanced response to formalin in later life, indicating that programming of stress and/or pain pathways has occurred as a result of these early life events. In addition to the development of a novel model of chronic pain, this study highlights the long-term impact that adverse perinatal events can have on offspring.